Format

Send to

Choose Destination
See comment in PubMed Commons below
Oncogene. 2015 Apr 16;34(16):2061-71. doi: 10.1038/onc.2014.153. Epub 2014 Jun 9.

PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling.

Author information

1
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Bringham and Women's Hospital and Harvard Medical School, Boston, MA, USA [3] Broad Institute of MIT and Harvard, Cambridge, MA, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
3
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Bringham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
6
1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Abstract

Targeting HER2 with antibodies or small molecule inhibitors in HER2-positive breast cancer leads to improved survival, but resistance is a common clinical problem. To uncover novel mechanisms of resistance to anti-HER2 therapy in breast cancer, we performed a kinase open reading frame screen to identify genes that rescue HER2-amplified breast cancer cells from HER2 inhibition or suppression. In addition to multiple members of the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) signaling pathways, we discovered that expression of the survival kinases PRKACA and PIM1 rescued cells from anti-HER2 therapy. Furthermore, we observed elevated PRKACA expression in trastuzumab-resistant breast cancer samples, indicating that this pathway is activated in breast cancers that are clinically resistant to trastuzumab-containing therapy. We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro-apoptotic protein BAD, the BCl-2-associated death promoter, thereby permitting survival signaling through BCL-XL. Pharmacological blockade of BCL-XL/BCL-2 partially abrogated the rescue effects conferred by PRKACA and PIM1, and sensitized cells to lapatinib treatment. These observations suggest that combined targeting of HER2 and the BCL-XL/BCL-2 anti-apoptotic pathway may increase responses to anti-HER2 therapy in breast cancer and decrease the emergence of resistant disease.

PMID:
24909179
PMCID:
PMC4261061
DOI:
10.1038/onc.2014.153
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center